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1.
Cancer Prev Res (Phila) ; 14(6): 675-682, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33782049

RESUMO

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm2, SD 620.7; placebo: +307.8 Ki67+ cells/mm2, SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus.Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK2 receptor antagonist did not have obvious chemopreventive effects.


Assuntos
Adenocarcinoma/prevenção & controle , Esôfago de Barrett/tratamento farmacológico , Benzodiazepinonas/administração & dosagem , Neoplasias Esofágicas/prevenção & controle , Compostos de Fenilureia/administração & dosagem , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Idoso , Esôfago de Barrett/patologia , Benzodiazepinonas/efeitos adversos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/patologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Esofagoscopia , Feminino , Gastrinas/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Receptor de Colecistocinina B/antagonistas & inibidores
2.
Clin Transl Sci ; 14(2): 664-670, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33340277

RESUMO

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Benzodiazepinonas/efeitos adversos , Imunoconjugados/efeitos adversos , Síndrome do QT Longo/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Benzodiazepinonas/administração & dosagem , Cardiotoxicidade/diagnóstico , Cardiotoxicidade/etiologia , Eletrocardiografia/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Imunoconjugados/administração & dosagem , Síndrome do QT Longo/induzido quimicamente , Masculino , Pessoa de Meia-Idade
3.
Rev. neurol. (Ed. impr.) ; 71(4): 143-150, 16 ago., 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-195462

RESUMO

INTRODUCCIÓN: Numerosos fármacos se han relacionado con el agravamiento de síntomas en pacientes con miastenia grave, pero hasta la fecha no existen estudios sobre la exposición a fármacos en estos pacientes. OBJETIVOS: Describir el consumo de fármacos y calcular la tasa anual de episodios de exacerbación en una cohorte de pacientes con miastenia grave, y explorar posibles factores de riesgo de exacerbaciones graves. PACIENTES Y MÉTODOS: Estudio observacional longitudinal retrospectivo que incluye a pacientes adultos con miastenia grave seguidos en consulta. Cálculo de frecuencias, tasas y construcción de modelo de eventos repetidos. RESULTADOS: De 91 pacientes incluidos, el 94,51% estuvo expuesto al menos a un fármaco durante el período de estudio (siete años y un mes). De ellos, 51 tuvieron al menos una prescripción de un fármaco contraindicado en la ficha técnica (56,04%). Se contabilizaron 145 exacerbaciones en 50 pacientes. La tasa anual de incidencia fue de 0,35 exacerbaciones por paciente y año. De estas exacerbaciones, 48 fueron graves (en 18 pacientes), con una tasa anual de incidencia de 0,12. Se halló una posible asociación entre diagnóstico de miastenia grave generalizada y timectomía, con un aumento del riesgo de episodios de exacerbación graves. CONCLUSIONES: En esta cohorte se encontró una amplia exposición a fármacos, pero no asociación con el riesgo de episodios de exacerbación graves. Algo más de la mitad de pacientes tuvo al menos un episodio de exacerbación durante el período de estudio, la mayoría leves. Son necesarios estudios que corroboren estas conclusiones y puedan estudiar posibles correlaciones entre fármacos y el riesgo de episodios de exacerbación


INTRODUCTION: Numerous drugs have been related to exacerbation of myasthenia gravis. So far there are no studies examining the extent of use of drugs related to exacerbation of myasthenia gravis. AIMS: We sought to assess the extent of use of drugs related to exacerbations and the annual incidence rate of exacerbations in a cohort of myasthenia gravis patients. We explored possible risk factors of severe exacerbations. PATIENTS AND METHODS: We performed a retrospective cohort study. We included adult patients followed in neurology department. We estimated frequencies, rates and built a recurrent events model. RESULTS: We included 91 patients. 94.51% of patients had at least one prescription of a drug. 51 patients had at least one prescription of a drug contraindicated according to its drug label. 145 exacerbation episodes were reported in 50 patients. The annual incidence rate of exacerbation episodes was 0.35. 48 exacerbations were severe (in 18 patients). The annual incidence rate of severe exacerbation episodes was 0.12. Generalized myasthenia gravis and thymectomy were associated with a higher risk of severe exacerbation episodes. CONCLUSIONS: Our patients were extensive and widespread exposed to drugs during the follow-up period but we did not find and association with severe exacerbation episodes. Just over half of the patients had at least one exacerbation episode during the study period, most of them were mild. Further studies with larger sample sizes are necessary to corroborate these conclusions and to study possible correlations between the use of drugs and the risk of exacerbation episodes


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Miastenia Gravis/induzido quimicamente , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miastenia Gravis/fisiopatologia , Fatores de Risco , Estudos Longitudinais , Estudos Retrospectivos , Timectomia/estatística & dados numéricos , Intervalos de Confiança , Benzodiazepinonas/efeitos adversos
5.
Lung Cancer ; 135: 145-150, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31446987

RESUMO

OBJECTIVES: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. MATERIALS AND METHODS: Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. RESULTS: Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. CONCLUSIONS: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Benzodiazepinonas/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/farmacocinética , Feminino , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Japão , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Recidiva , Carcinoma de Pequenas Células do Pulmão/mortalidade , Resultado do Tratamento
7.
Drugs R D ; 18(4): 255-258, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30232719

RESUMO

Small cell lung cancer (SCLC) comprises about 15% of all cases of lung cancer. In recent years, owing to a change in the epidemiology of smoking habits, the incidence of the tumor has decreased; however, it remains a significant challenge to global health. While the tumor has a favorable initial response to chemoradiation, relapse is invariable, and second-line regimens may be intolerable given the severity of side effects. For patients with tumors resistant to second-line regimens, no current standard regimens exist. Rovalpituzumab tesirine is a novel antibody-drug conjugate, targeting delta-like protein 3, fundamental in the downstream cellular signaling for proliferation and apoptosis. This drug is reported to have shown promise in pre-clinical and phase I trials. It appears effective in decreasing tumor burden and is reported to be well tolerated, albeit with a significant adverse effect profile. Currently, it is being studied as part of initial and subsequent line chemotherapeutic regimens; it remains to be seen if this is a viable option in the treatment of SCLC. This may add to the agents that can be used against SCLC, and help improve outcomes.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , Imunoconjugados/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/química , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/química , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia
9.
Br J Clin Pharmacol ; 83(3): 466-475, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27704617

RESUMO

AIMS: Netazepide, a gastrin/cholecystokinin 2 receptor antagonist, once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalized circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours. The aim was to assess whether longer-term netazepide treatment can eradicate type 1 gastric NETs. METHODS: After a mean 14 months off netazepide, 13 of the 16 patients took it for another 52 weeks. Assessments were: gastroscopy; gene-transcript expression in corpus biopsies using quantitative polymerase chain reaction; blood CgA and gastrin concentrations; and safety assessments. RESULTS: While off-treatment, the number of tumours, the size of the largest one, and CgA all increased again. Netazepide for 52 weeks: cleared all tumours in 5 patients; cleared all but one tumour in one patient; reduced the number of tumours and size of the largest one in the other patients; normalized CgA in all patients; and reduced mRNA abundances of CgA and histidine decarboxylase in biopsies. Gastrin did not increase further, confirming that the patients had achlorhydria. Netazepide was safe and well tolerated. CONCLUSIONS: A gastrin/cholecystokinin 2 receptor antagonist is a potential medical and targeted treatment for type 1 gastric NETs, and an alternative to regular gastroscopy or surgery. Treatment should be continuous because the tumours will regrow if it is stopped. Progress can be monitored by CgA in blood or biomarkers in mucosal biopsies.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Benzodiazepinonas/uso terapêutico , Gastrite Atrófica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Acloridria/complicações , Acloridria/tratamento farmacológico , Acloridria/metabolismo , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/complicações , Benzodiazepinonas/efeitos adversos , Cromogranina A/biossíntese , Cromogranina A/sangue , Gastrinas/sangue , Gastrite Atrófica/sangue , Gastrite Atrófica/complicações , Histidina Descarboxilase/biossíntese , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/metabolismo , Compostos de Fenilureia/efeitos adversos
10.
Pharmacology ; 96(5-6): 240-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26382237

RESUMO

BACKGROUND/AIMS: LRRK2 (leucine-rich repeat protein kinase 2) is one of the most commonly accepted genes associated with Parkinson's disease (PD). The overexpression of disease-associated mutations in LRRK2 is toxic to the cells, while reduction or elimination of LRRK2 expression promotes cell health and growth. Thus, the identification of an LRRK2 inhibitor with good physiochemical and pharmacokinetic properties is of great interest for the treatment of PD. METHODS: In this study, we have investigated LRRK2 compounds, LRRK2-IN-1 and Compound 1, in vitro and in vivo to determine how suitable they are as a selective LRRK2 tool compound. RESULTS: We report that Compound 1, patented by GSK, is a potent and selective LRRK2 inhibitor with good blood-brain barrier permeability as reflected by its high brain to plasma ratio in rats. In addition, Compound 1 can significantly promote neurite outgrowth in a primary cortical culture, indicating an optimistic cellular function of this compound in a biological system. In contrast, LRRK2-IN-1 is a less selective LRRK2 inhibitor and has low brain penetration. Furthermore, LRRK2-IN-1 is cyto- and genotoxic, while Compound 1 does not exhibit any toxicity. CONCLUSIONS: These results suggest that Compound 1 may be a superior tool compound than LRRK2-IN-1 to advance future pharmacological research on LRRK2.


Assuntos
Benzodiazepinonas/farmacologia , Descoberta de Drogas/métodos , Doença de Parkinson/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/sangue , Benzodiazepinonas/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Doença de Parkinson/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/genética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Ratos Sprague-Dawley , Especificidade por Substrato , Distribuição Tecidual
11.
Biochem Pharmacol ; 97(1): 51-61, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26212540

RESUMO

Microtubules are critical elements that are involved in a wide range of cellular processes, and thus, they have become an attractive target for many anticancer drugs. A novel synthesised compound, 12P, was identified as new microtubule inhibitor. This compound inhibits tubulin polymerisation through binding to the colchicine-binding site of tubulin. 12P exhibits excellent anti-proliferative activities against a panel of human cancer cell lines, with IC50 values range from 9 to 55nM. Interestingly, compound 12P also displayed equally potent cytotoxicity against several drug-resistant cell lines, and it showed high selectivity for active human umbilical vein endothelial cells (HUVECs). Further flow cytometric analysis showed that 12P induces G2/M phase arrest and apoptosis in A549 cells. Cellular studies have revealed that the induction of apoptosis by 12P was associated with a collapse of mitochondrial membrane potential (MMP), accumulation of reactive oxygen species (ROS), alterations in the expression of some cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis-related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Importantly, 12P significantly reduced the growth of xenograft tumours of A549 cells in vivo (tumour inhibitory rate of 12P: 84.2%), without any loss of body weight. Taken together, these in vitro and in vivo results suggested that 12P may become a promising lead compound for the development of new anticancer drugs.


Assuntos
Antineoplásicos/uso terapêutico , Benzodiazepinonas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Microtúbulos/efeitos dos fármacos , Organofosfatos/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/química , Benzodiazepinonas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Resistencia a Medicamentos Antineoplásicos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/química , Drogas em Investigação/farmacologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Organofosfatos/efeitos adversos , Organofosfatos/química , Organofosfatos/farmacologia , Distribuição Aleatória , Estilbenos/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/efeitos adversos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Br J Clin Pharmacol ; 79(5): 744-55, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25335860

RESUMO

AIMS: To compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. METHODS: Thirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. RESULTS: All treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. CONCLUSIONS: Netazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions.


Assuntos
Benzodiazepinonas/farmacologia , Ácido Gástrico/metabolismo , Compostos de Fenilureia/farmacologia , Rabeprazol/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Estômago , Adulto , Idoso , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Gastrinas/sangue , Voluntários Saudáveis , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Rabeprazol/administração & dosagem , Rabeprazol/efeitos adversos , Rabeprazol/sangue , Estômago/efeitos dos fármacos , Estômago/patologia , Adulto Jovem
13.
Br J Clin Pharmacol ; 76(5): 680-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23432415

RESUMO

AIM: To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24 h gastric pH and plasma gastrin. METHOD: We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100 mg 12 hourly, omeprazole 20 mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ≥ 4 during 0-4, 4-9, 9-13 and 13-24 h after the morning dose, and by plasma gastrin. P < 0.05 was significant. RESULTS: Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9-13 h after the 100 mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. CONCLUSION: Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.


Assuntos
Benzodiazepinonas/farmacologia , Gastrinas/sangue , Omeprazol/farmacologia , Compostos de Fenilureia/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Adulto , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Determinação da Acidez Gástrica , Humanos , Concentração de Íons de Hidrogênio , Masculino , Omeprazol/administração & dosagem , Omeprazol/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacologia , Fatores de Tempo , Adulto Jovem
14.
Br J Clin Pharmacol ; 76(5): 689-98, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23432534

RESUMO

AIMS: To confirm by means of pentagastrin, a synthetic gastrin agonist, that netazepide is a gastrin/CCK2 receptor antagonist in healthy subjects, and that antagonism persists during repeated dosing. METHODS: We did two studies in which we infused pentagastrin (0.6 µg kg(-1) h(-1) intravenously), aspirated gastric secretion and measured the volume, pH and H(+) secretion rate of the gastric aspirate. First, we did a double-blind, five-way crossover study (n = 10) to assess the effect of single oral doses of netazepide (1, 5, 25 and 100 mg) and placebo on the response to pentagastrin. Then, we did a single-blind, placebo-controlled study (n = 8) to assess the effect of the first and last oral doses of netazepide (100 mg) twice daily for 13 doses on the response to pentagastrin. RESULTS: Netazepide was well tolerated. After placebo, pentagastrin increased the volume and H(+) secretion rate and reduced the pH of gastric aspirate. Compared with placebo, single doses of netazepide caused dose-dependent inhibition of the pentagastrin response (P < 0.02); netazepide (100 mg) abolished the response. After 13 doses, the reduction in volume and H(+) secretion rate persisted (P < 0.001), but the pH effect was mostly lost. CONCLUSIONS: Netazepide is an orally active, potent, competitive antagonist of human gastrin/CCK2 receptors. Antagonism is dose dependent and persists during repeated dosing, despite tolerance to the effect on pH. Further studies are required to explain that tolerance. Netazepide is a tool to study the physiology and pharmacology of gastrin, and merits studies in patients to assess its potential to treat gastric acid-related conditions and the trophic effects of hypergastrinaemia.


Assuntos
Benzodiazepinonas/farmacologia , Gastrinas/metabolismo , Pentagastrina/farmacologia , Compostos de Fenilureia/farmacologia , Receptor de Colecistocinina B/antagonistas & inibidores , Administração Oral , Adulto , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Método Simples-Cego , Adulto Jovem
15.
Clin Cancer Res ; 17(11): 3794-802, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21346148

RESUMO

PURPOSE: This phase I study assessed the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of SJG-136, a sequence-specific DNA cross-linking agent, in patients with advanced cancer. EXPERIMENTAL DESIGN: In schedule A, seven patients received escalating doses of SJG-136 (6, 12, 24, and 48 µg/m(2)) daily for 5 of 21 days. Blood samples were collected for PK analysis on days 1 and 5 of cycle 1. In schedule B, SJG-136 was given daily for 3 of 21 days (N = 17; doses 20, 25, 30, and 35 µg/m(2)). Blood samples were collected on days 1 and 3 of cycles 1 and 2 for PK and PD analysis. Patients in schedule B received dexamethasone and early diuretic care. RESULTS: Schedule A-dose-limiting toxicities included grade 3 edema, dyspnea, fatigue, and delayed liver toxicity (grade 3-4). PK analysis revealed dose-dependent increases in AUC and C(max). Substantial changes in volume of distribution at steady-state occurred after repeated dosing in some patients prior to the onset of edema. Schedule B-the same toxicities were manageable with steroid premedication and diuretic support. No significant myelosuppression occurred on either schedule. DNA interstrand cross-links correlated with systemic exposure of SJG-136 following the second dose in cycle 1 and were still detectable immediately before cycle 2. CONCLUSIONS: The MTD of SJG-136 in this study was 30 µg/m(2) administered on a daily 3× basis with no myelosuppression effects. Coupled with supportive management, SJG-136 is now advancing to a phase II trial in ovarian cancer.


Assuntos
Benzodiazepinonas/farmacologia , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Pirróis/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/metabolismo , Benzodiazepinonas/farmacocinética , Dexametasona/administração & dosagem , Dispneia/induzido quimicamente , Edema/induzido quimicamente , Fadiga/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirróis/efeitos adversos , Pirróis/metabolismo , Pirróis/farmacocinética
16.
Cancer Chemother Pharmacol ; 65(5): 833-8, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19672598

RESUMO

PURPOSE: SJG-136 is a pyrrolobenzodiazepine dimer that forms DNA crosslinks and has demonstrated broad antitumor activity. We undertook this trial to determine the maximum-tolerated dose (MTD), toxicities and pharmacokinetic (PK) profile of SJG-136 in patients with an advanced solid tumor. PATIENTS AND METHODS: In this phase I study, patients were treated with SJG-136 on days 1, 8 and 15 of a 28-day cycle. Dose levels studied were 10, 20, 40 and 60 microg/m2. PK parameters of SJG-136 were assessed following the intravenous administration of SJG-136 on days 1 and 15 of cycle 1. RESULTS: Twenty-one patients with advanced solid tumors were treated. Patients had a median of two prior chemotherapy regimens. Fatigue was dose-limiting with SJG-136 60 microg/m2/day administered on days 1, 8 and 15 of a 28-day cycle. Grade 3 thrombocytopenia and delayed onset liver toxicity were seen in one patient each. PK parameters of SJG-136 indicated dose-proportional increases in systemic exposure with increasing doses. No objective responses were seen. CONCLUSION: For patients with advanced solid tumors, the MTD of SJG-136 is 40 microg/m2/day administered on days 1, 8 and 15 of a 28-day cycle. The major dose limiting toxicity was fatigue. Alternative dosing strategies are now being evaluated.


Assuntos
Antineoplásicos/administração & dosagem , Benzodiazepinonas/administração & dosagem , Pirróis/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Relação Dose-Resposta a Droga , Esquema de Medicação , Tolerância a Medicamentos , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Pirróis/efeitos adversos , Pirróis/farmacocinética , Neoplasias da Bexiga Urinária/tratamento farmacológico
17.
Eur J Cancer ; 46(3): 526-33, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20006921

RESUMO

AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Receptor de Colecistocinina B/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/sangue , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/sangue , Feminino , Gastrinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/sangue , Qualidade de Vida , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento , Gencitabina
18.
Clin Cancer Res ; 15(6): 2140-7, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19276288

RESUMO

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.


Assuntos
Antineoplásicos/uso terapêutico , Benzodiazepinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Benzodiazepinonas/efeitos adversos , Benzodiazepinonas/farmacocinética , DNA/metabolismo , Histonas/análise , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirróis/efeitos adversos , Pirróis/farmacocinética
19.
Neurosci Lett ; 332(3): 210-2, 2002 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-12399016

RESUMO

To investigate the safety and tolerability of L-365,260 in human subjects taking morphine for intractable pain. An open label study of nine adult subjects. Two doses of L-365,260 were administered to all subjects separated by a 4 h interval (three received 10 mg, three 30 mg and three 60 mg). Haemodynamic and respiratory variables were recorded from immediately prior to first drug administration to T + 600 min. In addition, continuous electrocardiogram (ECG) monitoring and serial 12 lead ECGs were recorded along with pain and side effect measurements. No major side effects were observed. L-365,260 was well tolerated. No abnormalities in blood pressure, heart rate, respiratory rate or ECG measurements were recorded. Minor side effects were observed. L-365,260 can be safely administered at the doses investigated to human subjects receiving morphine for intractable pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Benzodiazepinonas/uso terapêutico , Morfina/uso terapêutico , Dor Intratável/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Receptores da Colecistocinina/antagonistas & inibidores , Adulto , Analgésicos Opioides/efeitos adversos , Benzodiazepinonas/efeitos adversos , Preparações de Ação Retardada , Eletrocardiografia/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Morfina/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Receptor de Colecistocinina B , Mecânica Respiratória
20.
Epilepsia ; 39(10): 1115-8, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9776334

RESUMO

We report a case a carbamazepine (CBZ) intoxication with negative myoclonus that occurred 4 weeks after clobazam (CLB) had been added to a stable regimen of CBZ and topiramate (TPM). Both CBZ and CBZ-epoxide (CBZ-E) blood levels were elevated, and the symptoms resolved quickly when CBZ dosage was reduced and CLB discontinued. CLB was reintroduced a year later with the patient's consent, and the time course of the interaction was studied: CBZ and CBZ-E levels increased slowly over 12 days. The interaction is thus probably related to the progressive increase in Nor-CLB.


Assuntos
Ansiolíticos , Anticonvulsivantes/efeitos adversos , Benzodiazepinas , Benzodiazepinonas/efeitos adversos , Carbamazepina/intoxicação , Epilepsia/tratamento farmacológico , Mioclonia/induzido quimicamente , Idoso , Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Benzodiazepinonas/sangue , Benzodiazepinonas/uso terapêutico , Carbamazepina/sangue , Carbamazepina/uso terapêutico , Clobazam , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada , Eletroencefalografia/efeitos dos fármacos , Epilepsia/sangue , Humanos , Masculino , Mioclonia/prevenção & controle
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